Genetic Variant NM_177977.3:c.1847C>A (chr17-41724714-G-T) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_177977.3(HAP1):c.1847C>A(p.Ser616*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,592,356 control chromosomes in the GnomAD database, including 1,738 homozygotes. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.062 ( 918 hom., cov: 32)

Exomes 𝑓: 0.0065 ( 820 hom. )

Consequence

HAP1
NM_177977.3 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0240

Publications

9 publications found

Variant links:

Genes affected

HAP1 (HGNC:4812): (huntingtin associated protein 1) Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with huntingtin, with two cytoskeletal proteins (dynactin and pericentriolar autoantigen protein 1), and with a hepatocyte growth factor-regulated tyrosine kinase substrate. The interactions with cytoskeletal proteins and a kinase substrate suggest a role for this protein in vesicular trafficking or organelle transport. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

HAP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 17-41724714-G-T is Benign according to our data. Variant chr17-41724714-G-T is described in ClinVar as [Benign]. Clinvar id is 1287515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAP1	NM_177977.3 link	c.1847C>A	p.Ser616*	stop_gained	Exon 11 of 11	ENST00000347901.9	NP_817084.2	P54257-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAP1	ENST00000347901.9 link	c.1847C>A	p.Ser616*	stop_gained	Exon 11 of 11	1	NM_177977.3	ENSP00000334002.4		P54257-2

Frequencies

GnomAD3 genomes

AF:

0.0615

AC:

9353

AN:

152080

Hom.:

913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0239

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.0407

GnomAD2 exomes

AF:

0.0163

AC:

4047

AN:

247714

AF XY:

0.0120

show subpopulations

Gnomad AFR exome

AF:

0.217

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.000103

Gnomad EAS exome

AF:

0.000598

Gnomad FIN exome

AF:

0.0000956

Gnomad NFE exome

AF:

0.000863

Gnomad OTH exome

AF:

0.00843

GnomAD4 exome

AF:

0.00652

AC:

9383

AN:

1440158

Hom.:

820

Cov.:

AF XY:

0.00561

AC XY:

3996

AN XY:

712162

show subpopulations

African (AFR)

AF:

0.219

AC:

7254

AN:

33056

American (AMR)

AF:

0.0122

AC:

539

AN:

44258

Ashkenazi Jewish (ASJ)

AF:

0.0000780

AC:

AN:

25634

East Asian (EAS)

AF:

0.000281

AC:

AN:

39168

South Asian (SAS)

AF:

0.000622

AC:

AN:

85260

European-Finnish (FIN)

AF:

0.0000761

AC:

AN:

52540

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

4604

European-Non Finnish (NFE)

AF:

0.000491

AC:

538

AN:

1096328

Other (OTH)

AF:

0.0153

AC:

910

AN:

59310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

407

814

1220

1627

2034

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0616

AC:

9374

AN:

152198

Hom.:

918

Cov.:

AF XY:

0.0587

AC XY:

4365

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.213

AC:

8839

AN:

41466

American (AMR)

AF:

0.0239

AC:

366

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00116

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68010

Other (OTH)

AF:

0.0402

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

392

784

1176

1568

1960

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0192

Hom.:

553

Bravo

AF:

0.0702

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.201

AC:

885

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.0200

AC:

2428

Asia WGS

AF:

0.0220

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 11, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23352160, 27884173) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.040

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Benign

0.92

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.22

PhyloP100

-0.024

Vest4

0.29

GERP RS

1.6

PromoterAI

-0.026

Neutral

(source)

Mutation Taster

=158/42

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_177977.3:c.1847C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over